Ligand-Promoted Pd(II)-Catalyzed Functionalization of Unactivated C(sp3)–H Bond: Regio- and Stereoselective Synthesis of Arylated Rimantadine Derivatives

Abstract

Stereoselective functionalization of the adamantyl bridge methylene C(sp3)–H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C(sp3)–H arylation/hetereoarylation of the antivirus drug rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, and a series of optically pure arylated rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that provides ample compound space for further pharmaceutical research.